[unreadable] This project was started late in the candidate's post-doctoral career and will require an additional training period to fully develop. The candidate proposes to use the extensive resources of Harvard University and his advisor, Dr. John Dowling, to become an independent, academic investigator in the addiction field. Dr. Dowling has a well-established record of success as both a scientist and as a mentor. His extensive fish facility as well as his expertise in examining dopaminergic mechanisms provides an ideal environment for the research proposal described below. In addition, interactions with groups examining similar questions in molecular genetics and behavioral neuroscience at Harvard, formal classes, teaching, and attending scientific meetings will all be used to provide the additional education and training required for the candidate to achieve independence. In particular, Dr. S. Barak Caine of the Department of Psychiatry at McClean hospital has agreed to serve as a consultant in the studies proposed. Dr. Caine is a behavioral neuroscientist examining reinforcement in drug addiction. The goal of this research proposal is to find genes that underlie some of the behavioral aspects of drug addiction. Zebra fish were chosen as a model organism because they are especially amenable to genetic manipulation and analysis and because they are also behaviorally responsive to cocaine. Specifically, they exhibit cocaine-induced conditioned place preference (CPP). Understanding CPP, a test traditionally used to model reward, may lend insight as to the development of addiction. The Dowling lab has generated large numbers of mutagenized zebra fish families, some of which have been screened using a CPP test for cocaine reinforcement. In addition, we have devised secondary screens for learning capacity and visual sensitivity to compliment the CPP studies. Thus far we found three families with a high number of fish unresponsive to cocaine in the CPP test. These preliminary results have prompted the following research proposal for which we have three specific aims. First, we propose to further characterize CPP in zebra fish by subtly changing the test parameters and by using dopaminergic antagonists together with cocaine. Second, we will continue screening families for abnormally low and high CPP. Finally, we will further characterize the current mutant candidates using additional behavioral tests, anatomical analysis and molecular genetics. [unreadable] [unreadable] [unreadable] [unreadable]